Since the inverse relationship between plasma high-density lipoprotein cholesterol (HDL-C) levels and the risk of coronary artery disease (CAD) have been well-established, it has always been a hot spot on how to regulate HDL-C levels for the treatment of CAD-related disease. High and low HDL levels are closely related to its own production and metabolism, which are primarily determined by corresponding regulatory genes. It has been suggested that plasma HDL-C levels have a strong inherited basis with heritability estimates of 40%～60%, showing the great significance in discussing variants causes associated with HDL-C levels. Candidate gene, genome-wide linkage, and most recently genome-wide association (GWA) studies have identified several genetic variations for plasma HDL-C levels. However, the functional role of some variants remains unknown, and they do not always have relation to the risk of CAD. This review will be summarized on the structure of HDL, its metabolism and production, as well as the genetic causes of high and low HDL-C. Notably, recent genetic findings from candidate gene and the GWA studies will be the focus of this text aiming at elucidating the important genetic factors affecting HDL-C concentrations. Comprehensive study on genetics conferring to high and low HDL-C levels using integrative approaches is essential to reveal their relationships with CAD and explore novel pathways on the treatment of CAD.